Cope Georgina, Golbang Amir, O'Shaughnessy Kevin M
Clinical Pharmacology Unit, Department of Medicine, University of Cambridge, Cambridge, UK.
Pharmacol Ther. 2005 May;106(2):221-31. doi: 10.1016/j.pharmthera.2004.11.010. Epub 2005 Jan 26.
The WNK kinases are a small group of serine/threonine kinases with unique catalytic domains that lack the lysine residue used in other kinases to co-ordinate ATP (hence, With No K [WNK]). Their closest homologues are found within the mitogen-activated protein kinase (MAPK) pathway suggesting a role in signalling. Two WNK isoforms, WNK1 and WNK4, have been identified as the disease genes for a rare monogenic hypertension syndrome (Gordon's syndrome or pseudohypoaldosteronism type 2 [PHA2]) implicating them in salt homeostasis by the kidney. This is supported by recent data showing widespread expression of WNK1 and WNK4 in mammalian transporting epithelia. Within the kidney, WNKs probably regulate the surface expression of several proteins involved in ion transport, including the sodium-chloride cotransporter (NCCT) and the potassium channel renal outer medullary potassium channel (ROMK), based on co-expression studies in Xenopus oocytes. WNKs, especially WNK4, have been suggested as candidate genes for essential hypertension itself, but evidence for this is lacking. Some of the effects of the WNKs are independent of their kinase function, suggesting that they are dependent on specific protein-protein interactions. It seems likely that the WNKs are part of much larger protein scaffolds in cells and have effects in cells beyond ion transport. However, because of their effect on expression of the NCCT they are attractive drug targets for the development of novel antihypertensive agents. These agents could potentially offer the efficacy of a thiazide diuretic, but without the metabolic side effects usually seen with this class of antihypertensive therapy.
WNK激酶是一小类丝氨酸/苏氨酸激酶，具有独特的催化结构域，缺少其他激酶中用于协调ATP的赖氨酸残基（因此称为无赖氨酸[WNK]）。在丝裂原活化蛋白激酶（MAPK）途径中发现了它们最接近的同源物，表明其在信号传导中起作用。两种WNK异构体，WNK1和WNK4，已被确定为一种罕见的单基因高血压综合征（戈登综合征或2型假性醛固酮增多症[PHA2]）的致病基因，这表明它们参与肾脏的盐稳态调节。最近的数据显示WNK1和WNK4在哺乳动物转运上皮细胞中广泛表达，支持了这一观点。在肾脏中，基于非洲爪蟾卵母细胞的共表达研究，WNK可能调节几种参与离子转运的蛋白质的表面表达，包括氯化钠共转运体（NCCT）和钾通道肾外髓质钾通道（ROMK）。WNK，尤其是WNK4，已被认为是原发性高血压的候选基因，但缺乏相关证据。WNK的一些作用与其激酶功能无关，表明它们依赖于特定的蛋白质-蛋白质相互作用。WNK似乎是细胞中更大的蛋白质支架的一部分，并且在细胞中的作用超出了离子转运。然而，由于它们对NCCT表达的影响，它们是开发新型抗高血压药物的有吸引力的药物靶点。这些药物可能具有噻嗪类利尿剂的疗效，但没有这类抗高血压治疗通常出现的代谢副作用。
